Insulin resistance and atherosclerosis.

Insulin resistance is a complex metabolic defect that has several causes dependent on an individual's genetic substrate and the underlying pathophysiologic state. Atherogenic dyslipidemia, hyperinsulinemia, dysglycemia, inflammation associated with obesity, and ectopic steatosis in liver and skeletal muscle all collude to facilitate endothelial dysfunction and predispose to the initiation and propagation of atherosclerosis. As aggressive management of the various risk factors does not seem to abrogate the so-called residual risk, more research is needed to define ways by which intervention can fundamentally alter the metabolic and vascular milieu and slow the pace of atherosclerosis, thus favorably affecting outcomes.

Biochemical basis and clinical consequences of glucolipotoxicity: a primer.

Both glucose and fatty acids may have good/adaptive or toxic/maladaptive actions on the pancreatic beta cell, depending on their concentrations. Hyperglycemia, via metabolic intermediates, may result in multiple cellular effects that are toxic to the pancreatic beta cell and indeed other tissues. While free fatty acids may affect cellular processes beyond lipid metabolism by interacting with transcription factors, triglyceride rich lipoproteins are endothelial cell-toxic and facilitate atherogenesis. The paradigm of "glucolipotoxicity" espouses that increased glucose and fatty acid levels act synergistically in causing toxicity to pancreatic islets and other organs, a process that eventually leads to the multiple defects seen in the metabolic syndrome and diabetes mellitus.

Effect of interface, height and density of long vertically aligned carbon nanotube arrays on their thermal conductivity: an experimental study.

The ever-growing need to dissipate larger amounts of heat from components and structures requires the development of novel materials with superior thermal conductivity. Aligned carbon nanotube arrays that are integrated in composite materials and structures may prove useful in increasing heat transfer through their thickness. Theoretical studies have shown the potential of carbon nanotubes to reach a thermal conductivity of 6600 Wm(-1)K(-1). Experimental results on the arrays however have shown much lower thermal conductivity values. A study was conducted to better understand heat conduction in mm-long carbon nanotube arrays and to experimentally determine their thermal conductivity. Emphasis was placed on the effect of various parameters including the height and density of the array and the thermal resistance at the array interface. A method was devised to measure the thermal conductivity of the array relying on Fourier's law while maintaining a steady state one-dimensional heat flow. The study reveals that the taller the array and the higher its density, the larger the thermal conductivity of the array. Quantitative data is also provided on the effect of various interface materials and their deposition technique on the thermal conductivity of the arrays.

Legacy effects from DCCT and UKPDS: what they mean and implications for future diabetes trials.

The United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Chronic Complications Trial (DCCT) are two landmark trials that convincingly demonstrated that tight glycemic control has beneficial effects on microvascular end points. These studies also revealed a "legacy effect," which is a sustained benefit with respect to cardiovascular disease outcomes seen long after the conclusion of the trial. We discuss possible molecular mechanisms that could play a role in causing the legacy effect.

Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease.

AIMS: Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD. METHODS: A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months. RESULTS: 27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment. CONCLUSIONS: Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

Objective measures of physical functional capacity warrant exploration to complement or replace the subjective physician estimated performance status.

Performance status, a measure of physical functioning, can be influenced by several undefined physician and patient-related factors, and is inherently subjective. Although disappointing results in phase 3 trials may reflect a lack of improved outcomes due to biological mechanisms, a confounding effect of imbalances of physical functioning cannot be excluded in the context of modest increments in antitumor activity. Therefore, performance status estimation may complicate drug development, and an objective measure of physical reserve is desirable and may complement or outperform performance status. We explore and discuss attractive candidates for objective measures of physical functioning.